Protein medications are the most rapidly expanding class of therapeutics, serving patients with diabetes, cancer, cardiovascular, renal, gastrointestinal, rheumatologic and neurological diseases, among many others. The therapeutic and commercial value of proteins as therapeutics including insulin, erythropoietin, G-CSF, plasminogen activator, and interferons is undisputed. Improved proteins or their formulations have enhanced the therapeutic efficacy of these parent products, by increasing their potency, time of action, and other properties.
Diabetes is a chronic disease characterized by either the inability of the body to produce insulin (Type I) or the failure to respond to it (Type II) (King, H., Aubert, R. E. & Herman, W. H. Global burden of diabetes, 1995-2025: Prevalence, numerical estimates, and projections. Diabetes Care 21, 1414-1431 (1998)). There is an emerging global epidemic of diabetes of both Type I and Type II forms. Nearly 1.1 million diabetics succumbed to death in 2005 (Dunstan, D. W., Zimmet, P. Z., Welborn, T. A., De Courten, M. P., Cameron, A. J., et al. The rising prevalence of diabetes and impaired glucose tolerance: The Australian Diabetes, Obesity and Lifestyle Study. Diabetes Care 25, 829-834 (2002)). Its economic consequences are even more staggering as people may live for years with diabetes, their cause of death is often recorded as heart diseases and kidney failures, both arising as a secondary consequence of diabetes. Restoring the normal metabolic milieu by administration of insulin from outside and thereby minimizing the risk of secondary complications has become an essential feature of diabetic treatment. The current therapy involves multiple daily subcutaneous (SC)/intramuscular (IM) injections of insulin, which leads to a heavy burden of compliance on patients. This in turn has led to alternative, less invasive routes of delivery. Attempts to exploit the nasal, oral, gastrointestinal and transdermal routes, have been mostly unsuccessful. Although a conventional insulin regimen for type I diabetes with twice-daily insulin injections is effective in controlling postprandial blood glucose levels, this treatment is of limited value due to its failure to control fasting hyperglycemia. Patients with diabetes mellitus need insulin therapy to boost intrinsic insulin supply once or twice a day. Also, post-prandial glucose homeostasis is maintained through regular insulin injections before each meal. Intensive insulin therapy delays the onset and or slows the progression of secondary complications, yet patients remain at a high risk of fasting hypoglycemia. An insulin formulation which releases insulin in a controlled manner for long periods of time would free the patients from the need to administer multiple doses of insulin daily.